Children with chronic mucocutaneous candidiasis (CMC) experience recurrent infections with
. Moreover, immune dysregulation in the early life of these patients induces various autoimmune diseases and ...affects normal growth and development. The adaptive and innate immune system components play a significant role in anti-fungal response. This response is mediated through IL-17 production by T helper cells. Inborn errors in IL-17-mediated pathways or
. sensing molecules are known to cause CMC. In this review, we describe underlying immune mechanisms of monogenic primary immune deficiency disorders known to cause CMC. We will explore insights into current management of these patients and novel available therapies.
SUMMARY
This paper presents a mortar-based finite element formulation for modelling earthquake cycles and wear on rough faults governed by rate and state friction. The method allows large sliding on ...the fault and accounts for all stages in the earthquake cycle, using a variable time step size with a transition between quasi-static and fully dynamic time discretizations. Wear laws with linear and power law forms are discretized and implemented into the mortar method, as well as a minimum level of normal traction constraint to treat fault opening. We examine the effect of wear laws on the slip behaviour and near-fault stresses during simulations of earthquake cycles on rough faults. The simulations demonstrate that the implementation of wear allows more realistic modelling of the earthquake cycle without the development of unrealistically large stresses and with less reduction of earthquake magnitude with total fault slip. Moreover, the method enables to study the effects of roughness and fault slip on the gouge zone thickness.
Cogan’s syndrome (CS) is a rare autoimmune disorder characterized by audiovestibular dysfunction and ocular inflammation. Currently, there is no specific serum autoantibody used in the diagnostic ...workup of CS. Treatment is based on immunosuppressive agents, mainly corticosteroids as first-line choice. Recently, novel therapeutic modalities in CS have emerged. These include tumor necrosis factor-α inhibitors and other biologicals. Despite medical treatment, hearing loss may progress to irreversible bilateral profound SNHL in approximately half of CS patients resulting in candidacy for cochlear implantation (CI). Due to the inflammatory nature of the disease that is causing endosteal reaction with partial obliteration or complete neoossification of the intracochlear ducts, early CI is recommended. CI provides excellent and stable hearing rehabilitation with high score of word and sentence recognition. In this review, we will discuss different aspects of CS including clinical presentation, diagnosis, treatment, and future directives.
The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe hypersensitivity reaction. Up-to-date treatment is based on withdrawal of medication, supportive care, ...and immunosuppression using high-dose corticosteroid (CS) therapy. However, evidence-based data are lacking regarding second-line therapy for steroid-resistant or steroid-dependent patients.
We hypothesize that the interleukin (IL)-5 axis plays a critical role in the pathophysiology of DRESS; hence, inhibition of this signaling pathway could offer a potential therapy for steroid-dependent and/or steroid-resistant cases, and it may offer an alternative to CS therapy in certain patients more prone to CS toxicity.
Herein, we collected worldwide data on DRESS cases treated with biological agents targeting the IL-5 axis. We reviewed all cases indexed in PubMed up to October 2022 and performed a total analysis including our center experience with two additional novel cases.
A review of the literature yielded 14 patients with DRESS who were treated with biological agents targeting the IL-5 axis as well as our two new cases. Reported patients are characterized by a female-to-male ratio of 1:1 and a mean age of 51.8 (17-87) years. The DRESS-inducing drugs, as expected from the prospective RegiSCAR study, were mostly antibiotics (7/16), as follows: vancomycin, trimethoprim-sulfamethoxazole, ciprofloxacin, piperacillin-tazobactam, and cefepime. DRESS patients were treated with anti-IL-5 agents (mepolizumab and reslizumab) or anti-IL-5 receptor (IL-5R) biologics (benralizumab). All patients have clinically improved under anti-IL-5/IL-5R biologics. Multiple doses of mepolizumab were needed to achieve clinical resolution, whereas a single dose of benralizumab was often sufficient. Relapse was noted in one patient receiving benralizumab treatment. One patient receiving benralizumab had a fatal outcome, although mortality was probably related to massive bleeding and cardiac arrest due to coronavirus disease 2019 (COVID-19) infection.
Current treatment guidelines for DRESS are based on case reports and expert opinion. Understanding the central role of eosinophils in DRESS pathogenicity emphasizes the need for future implementation of IL-5 axis blockade as steroid-sparing agents, potential therapy to steroid-resistant cases, and perhaps an alternative to CS treatment in certain DRESS patients more prone to CS toxicity.
Dear Editor, Interleukin (IL)-5 is a pivotal factor in eosinophilic inflammation. It promotes eosinophil hematopoiesis, chemotaxis, and activation. The role of IL-5 in the pathogenesis of ...eosinophilic asthma has been extensively studied and demonstrated in human subjects, as well in murine models. Humanized monoclonal antibodies against IL-5 (mepolizumab and reslizumab) and IL-5 receptor α-subunit (IL-5Rα; benralizumab) have recently been introduced for the treatment of severe eosinophilic asthma. A number of clinical trials have also evaluated the efficacy of IL-5-modulating agents in eosinophilic granulomatosis with polyangiitis (EGPA). Consequently, subcutaneous administration of mepolizumab is currently approved for use in severe asthma, as well as for EGPA. Likewise, benralizumab is indicated for severe and refractory eosinophilic asthma in adults, albeit not yet for EGPA. Eosinophilic disorders, other than asthma, that have also been evaluated for IL-5-modulating therapy include chronic eosinophilic pneumonia and hyper-eosinophilic syndrome.
The efficacy of biological treatment for severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) has recently been demonstrated through double-blinded clinical trials. The aim of this ...study was to provide preliminary real-world experience regarding biological therapy for uncontrolled CRSwNP. The records of patients who received biological treatment in a tertiary medical center between the years 2019 to 2022 were retrospectively reviewed. Patients included in this study were eligible for biological treatment according to the EPOS 2020 criteria. Among patients who had their first follow-up visit <6 months from the treatment initiation, the Sino-Nasal Outcome Test 22 Questionnaire (SNOT-22) score had decreased by 22% (
= 0.01) and the nasal polyp score (NPS) had decreased by 48% (
= 0.05). Among patients who had their first follow-up visit ≥6 months from treatment initiation, the SNOT-22 score had decreased by 40% (
= 0.03) and the NPS had decreased by 39% (
= 0.1). The number of patients who needed systemic steroid treatment had decreased by 68% (
< 0.0001), and the number of patients who needed endoscopic sinus surgery had decreased by 74% (
< 0.0001). These findings correspond with the improvement of clinical symptoms observed in prior randomized clinical trials, thus showing the effectiveness of biologic medications in the treatment of severe CRSwNP in a real-life setting. Although further cohort studies are warranted, our study also suggests evaluating patients at follow-up visits mainly by quality-of-life aspects and investigating longer dosing intervals of dupilumab.
We study numerically the effects of fault roughness on the nucleation process during earthquake sequences. The faults are governed by a rate and state friction law. The roughness introduces local ...barriers that complicate the nucleation process and result in asymmetric expansion of the rupture, nonmonotonic increase in the slip rates on the fault, and the generation of multiple slip pulses. These complexities are reflected as irregular fluctuations in the moment rate. There is a large difference between first slip events in the sequences and later events. In the first events, for roughness amplitude br ≤ 0.002, there is a large increase in the nucleation length with increasing br. For larger values of br, slip is mostly aseismic. For the later events there is a trade‐off between the effects of the finite fault length and the fault roughness. For br ≤ 0.002, the finite length is a more dominant factor and the nucleation length barely changes with br. For larger values of br, the roughness plays a larger role and the nucleation length increases significantly with br. Using an energy balance approach, where the roughness is accounted for in the fault stiffness, we derive an approximate solution for the nucleation length on rough faults. The solution agrees well with the main trends observed in the simulations for the later events and provides an estimate of the frictional and roughness properties under which faults experience a transition between seismic and aseismic slip.
Key Points
We study numerically the effects of fault roughness on the nucleation process during earthquake sequences
Roughness complicates the nucleation process with asymmetric expansion of the rupture, multiple slip pulses, and larger nucleation length
We derive an approximate solution for the nucleation length, which provides the roughness conditions under which faults can slip seismically
Background
The mRNA-based COVID-19 vaccine was introduced to the general public in December 2020. Shortly thereafter, safety concerns were raised due to the reporting of allergic reactions. ...Allergy-related disorders were suspected to be significant risk factors and the excipient polyethylene glycol was suggested to be a robust allergen.
Methods
This is a retrospective study analysis. Subjects with putative risk factors for severe allergic reactions to the Pfizer-BioNTech BNT162b2 vaccine were referred for vaccination under observation at the Unit of Allergy and Clinical Immunology. Data was collected for each subject, including demographic details, medical history and previous reactions to any allergen. When appropriate, skin tests were done prior to vaccination.
Results
A total of 346 subjects received 623 vaccine doses under observation. The study included patients with various allergy-related disorders (n=290) and those with allergy to a previous COVID-19 vaccine dose (n=56). Both groups showed female predominance (78% and 88%, p=NS). Patients without reactions to previous doses reported more drug allergy (80% vs. 39%, p<0.001) and previous anaphylaxis (64% vs. 14%, p<0.001). There was no difference in sensitivity to other allergens, including polyethylene glycol. Under observation, mild allergic reactions were noted in 13 individuals characterized by female gender (100%), a history of anaphylaxis (69%) and drug allergy (62%). In 7 subjects, allergy was treated with antihistamines while others recovered spontaneously.
Conclusion
Our study demonstrates that vaccination under specialist-supervision is a powerful tool for reducing over-diagnosis of systemic reactions and for rapid and reliable collection of vaccine safety data.
The Hadassah Medical Organization operates two hospitals in Jerusalem. During the COVID-19 pandemic it made an administrative decision to operate one hospital as a COVID-19 treatment hospital (CTH) ...and to have the second function as a non-COVID-19 treating hospital (NCTH) offering general medical services. The purpose of this study was to assess how this decision affected hospital worker anxiety.
From April 27 to May 1, during the COVID-19 pandemic in Israel, while the country was under lock-down, an electronic questionnaire survey was carried out among hospital workers of the CTH and NCTH. The questionnaire includes personal demographics and attitudes about COVID-19 and assesses present anxiety state using the State-Trait Anxiety Inventory for Adults (STAI-S) validated questionnaire. A STAI-S score of ≥45 was considered to represent clinical anxiety.
Completed questionnaires were received from 1570 hospital employees (24%). 33.5% of responders had STAI-S scores ≥45. Multivariable regression analysis showed that being a resident doctor (odds ration OR 2.13; 95% CL, 1.41-3.23; P = 0.0003), age ≤ 50 (OR, 2.08; 95% Cl, 1.62-2.67; P < .0001), being a nurse (OR, 1.29; 95% CL, 1.01-1.64; P = 0.039), female gender (OR, 1.63; 95% CL, 1.25-2.13; P = 0.0003) and having risk factors for COVID-19 (OR, 1.51; 95% CL, 1.19-1.91; P = 0.0007), but not hospital workplace (p = 0.08), were associated with the presence of clinical anxiety. 69% of the responders had been tested for COVID-19, but only nine were positive. CTH workers estimated that the likelihood of their already being infected with COVID-19 to be 21.5 ± 24.7% as compared to the 15.3 ± 19.5% estimate of NCTH workers (p = 0.0001). 50% (545/1099) of the CTH workers and 51% (168/330) of the NCTH workers responded that the most important cause of their stress was a fear of infecting their families (p = 0.7).
By multivariable analysis the creation of a NCTH during the COVID-19 pandemic was not found to be associated with a decrease in the number of hospital workers with clinical anxiety. Hospital worker support resources can be focused on the at-risk groups identified in this study.
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